Second International Neuroacanthocytosis Symposium: April 18th-19th 2005, Montreal Neurological Hospital and Institute
On Monday morning, we were welcomed by Eva Andermann and other McGill University dignitaries. Joseph Martin, Dean of Harvard Medical School, gave the keynote address, reviewing the pathways leading to degeneration of neurons in the major neurodegenerative disorders. Kailash Bhatia outlined the many possible clinical causes of chorea, stressing that family history, brain imaging and documentation of other symptoms are all necessary for a correct diagnosis. Adrian Danek and Glenn Irvine closed the session by updating us on the major scientific and fundraising developments in NA since the first symposium was held in 2001.
The second session concerned acanthocytosis and neurological disease. Gordon Stewart discussed stomatocytosis, a red blood cell abnormality that is considered the ‘reverse' of acanthocytosis. Rob Hegele reviewed abetalipoproteinemia and homozygous hypobetalipoproteinemia, two disorders of fat absorption that lead to neuroacanthocytosis. Giel Bosman detailed how acanthocytes show structural alterations in band 3, an abundant red cell protein. Michael Hayden outlined how therapeutic trials in Huntington's disease may be relevant to NA research. Ruth Walker presented the clinical features of Huntington's disease-like 2 (HDL2), a neurodegenerative disorder in which some patients show acanthocytosis.
Session 3 dealt with McLeod syndrome (MLS). Colvin Redman reviewed Kell, a blood group protein that binds to XK, the McLeod syndrome protein. Soohee Lee reported two human genes related to XK , XPLAC and XTES change to two related genes XPLAC and XTES, noting that their proteins are similar but are present in different tissues. Hans Jung detailed the clinical aspects of MLS, including the neuromuscular and brain imaging findings observed in this disorder. Steven Holland reviewed chronic granulomatous disease (CGD). CGD patients sometimes carry XK deletions, but may not survive long enough to develop MLS symptoms.
Monday's final session discussed aspects of chorea-acanthocytosis (ChAc). Carol Dobson-Stone presented the range of gene mutations that lead to ChAc, and a protein test that may aid in its diagnosis. Adrian Danek summarised the clinical information available for 106 gene-confirmed ChAc patients, the largest patient group yet described. Eva Andermann presented four French Canadian ChAc families who have probably inherited the same mutation from a common ancestor. Mio Ichiba concluded by reporting a Japanese family with an unusual inheritance pattern of ChAc, with alterations in the Huntington's disease gene, which may or may not be related to expression of ChAc.
Tuesday commenced with a session on pathology of biological systems in NA. Marie-Francoise Chesselet discussed the basal ganglia, the brain regions implicated in neuroacanthocytosis, and how dysfunction in different circuits within these regions may lead to different movement disorders. Klaus Leenders demonstrated altered brain cell activity in two ChAc patients at different stages of the disease. Francois Tison presented data on sleep patterns in NA, demonstrating fragmented sleep and poor sleep efficiency in three ChAc and two MLS patients.
The next session looked at the relationship between movement disorders and epilepsy. Renzo Guerrini reported the co-occurrence of epilepsy and paroxysmal dyskinesia in some families, suggesting that the same gene may be responsible. Frederick Andermann reported ChAc families where epilepsy occurred years before other symptoms, which complicated the diagnosis in these patients. Massimo Avoli reviewed the evidence for the function of interactions within the thalamo-cortical brain regions in the generation of epilepsy. Karen Gale concluded by considering the possible causes of epilepsy in subcortical brain regions.
Tuesday's third session was concerned with the biology of ChAc and HDL2. VPS13A , the ChAc gene, encodes a protein called chorein. Bob Fuller presented evidence that Vps13, the yeast protein related to chorein, is involved in transport of proteins within the cell – suggesting a similar role for chorein in humans. Antonio Velayos Baeza discussed the human family of proteins related to chorein, and Clotilde Levecque continued with data on chorein's potential binding partners. Russell Margolis concluded with results suggesting that aggregation of mutant mRNA is a major biological cause of HDL2.
The penultimate session was entitled, ‘Therapy and pressing needs'. Abbas Sadikot discussed the use of ‘deep brain stimulation' to alleviate symptoms in certain patients with severe movement disorders. Pierre Burbaud reported three NA patients who showed a reduction in some, but not all, symptoms after this treatment. Jacqueline McIntosh reported on work with a ChAc patient to overcome speech and feeding problems, focusing on compensation and disability management. The subsequent round table discussion considered goals for 2005, including banking of tissue samples and clinical data, to create a ‘virtual institute' for NA research.
The closing session discussed the utility of different organisms as models for studying NA. Akira Sano presented a mouse with a deletion in the ChAc gene, which has acanthocytes and abnormal gait - showing important similarities with human ChAc patients. Jim Phelan discussed how a nematode worm with abnormalities in clearance of dead cells could help elucidate the function of the McLeod gene. Finally, Juan Botas talked about how the fruit fly can be used to identify ‘modifier' genes involved in neurodegenerative pathways.
Overall, the two days we spent in Montreal were most fruitful and thought-provoking. Listening to professionals from such diverse backgrounds as genetics, clinical practice and cell biology highlighted that there are lessons to be learned from all fields of NA research. This meeting, as the previous one in Seeon in 2001, was quite extraordinary in the way that researchers who would never normally be in the same room were able to meet and exchange ideas. Combining this expertise in collaborative, multidisciplinary endeavours is vital to make the most significant advances in future research into these disorders.
The meeting was supported by the Movement Disorder Society, Montreal Neurological Hospital and Institute, McGill University , the High Q Foundation, Inc., John Grooms and numerous contributions from patients, their families and friends who support the Advocacy for Neuroacanthocytosis Patients.
Comments from participants
“It was one of the most unusual meetings I have ever attended given the combination of clinical and basic science as well as the highly intense focus of the meeting. I found it quite inspiring and we (myself and graduate student Leah Parkinson) definitely plan to intensify our work on yeast Soi1/Vps13 based on what we learned.”
Robert S. Fuller, Ph.D.
Professor and Associate Chair of Biological Chemistry
“From my own point of view it was striking how the themes that I outlined in
my talk (trafficking, membrane proteases, cholesterol) were repeated in
other ways by other investigators and clearly there is common ground.
There is also band 3, which I didn't talk about. One could make a
hypothesis based on the idea of trafficking of band 3/other membrane
molecules controlled by/involving a protease, based on cholesterol-rich
parts of the membrane.”
Gordon Stewart, MD FRCP,
Department of Medicine,
University College London
“I enjoyed every aspect of the meeting, both personally and professionally, and came away with many pleasant memories and a renewed scientific commitment to understanding the neuroacanthocytosis diseases.”
Jim Phelan, Ph.D.
University of Zurich
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